Organic compounds

ABSTRACT

A pharmaceutical composition for treatment of pain, comprises in combination a benzothiadiazole derivative as defined and a COX-2 inhibitor for simultaneous, sequential or separate use. Also provided is a method of treating a patient suffering from pain, comprising administering to the patient an effective amount of a benzothiadiazole derivative as defined and an effective amount of a COX-2 inhibitor.

This invention relates to COX-2 inhibitors, in particular to combineduse of COX-2 inhibitors with muscle relaxants, and compositionscontaining such combinations.

Accordingly the invention provides a pharmaceutical composition fortreatment of pain, which comprises in combination a benzothiadiazolederivative of formula I

wherein each R1, R2 and R3 independently, is hydrogen, halogen, C₁-C₇alkyl, C₁-C₇ alkoxy, nitro, cyano, hydroxy or C₁-C₇ alkylthio; and aCOX-2 inhibitor for simultaneous, sequential or separate use.

Further the invention provides the use of a COX-2 inhibitor for thepreparation of a medicament, for use in combination with abenzothiadiazole derivative of formula I as defined above, for treatmentof pain.

In the alternative the invention provides use of a benzothiadiazolederivative of formula I as defined above, for the preparation of amedicament for use in combination with a COX-2 inhibitor for treatmentof pain.

In a further aspect the invention provides a method of treating apatient suffering from pain comprising administering to the patient aneffective amount of a benzothiadiazole derivative of formula I asdefined above, and an effective amount of a COX-2 inhibitor.

In yet further aspects the invention provides:

-   -   (i) A package comprising a benzothiadiazole derivative of        formula I as defined above, together with instructions for use        in combination with a COX-2 inhibitor for treatment of pain, or    -   (ii) A package comprising a COX-2 inhibitor together with        instructions for use in combination with a benzothiadiazole        derivative of formula I as defined above, for treatment of pain.

Pain in general may be treated in accordance with the present inventionincluding both nociceptive and inflammatory pain. In particular thecombination treatment of the invention may be used for the treastment ofmusculoskeletal pain, especially lower back pain.

In the present description the terms “treatment” or “treat” refer toboth prophylactic or preventative treatment as well as curative ordisease modifying treatment, including treatment of patients at risk ofsuffering pain as well as patients who are already suffering pain.

In formula halogen preferably signifies bromine or chlorine.

The compounds of formula I are capable of tautomerisation and use of thetautomers thereof is included within the scope of the invention.

Preferred compounds of formula I include:

7-chloro-4-(2-imidazolin-2-yl-amino)-2,1,3,-benzothiadiazole;

4-(2-imidazolin-2-yl-amino)-7-methyl-2,1,3,-benzothiadiazole;

7-chloro-4-(2-imidazolin-2-yl-amino)-5-methyl-2,1,3,-benzothiadiazole;

5,7-dimethyl-4-(2-imidazolin-2-yl-amino)-2,1,3,-benzothiadiazole;

5-chloro-4-(2-imidazolin-2-yl-amino)-7-methyl-2,1,3,-benzothiadiazole;

5,7-dichloro-4-(2-imidazolin-2-yl-amino)-2,1,3,-benzothiadiazole;

5,6-dimethyl-4-(2-imidazolin-2-yl-amino)-2,1,3,-benzothiadiazole;

7-hydroxy-4-(2-imidazolin-2-yl-amino)-2,1,3,-benzothiadiazole;

5,6-dichloro-4-(2-imidazolin-2-yl-amino)-2,1,3,-benzothiadiazole;

6,7-dichloro-4-(2-imidazolin-2-yl-amino)-2,1,3,-benzothiadiazole;

4-(2-imidazolin-2-yl-amino)-7-methoxy-2,1,3,-benzothiadiazole;

5-bromo-7-chloro-4-(2-imidazolin-2-yl-amino)-2,1,3,-benzothiadiazole;

7-bromo-5-chloro-4-(2-imidazolin-2-yl-amino)-2,1,3,-benzothiadiazole;

4-(2-imidazolin-2-yl-amino)-2,1,3,-benzothiadiazole;

4-(2-imidazolin-2-yl-amino)-5-methyl-2,1,3,-benzothiadiazole;

4-(2-imidazolin-2-yl-amino)-5-chloro-2,1,3,-benzothiadiazole;

4-(2-imidazolin-2-yl-amino)-5-methoxy-2,1,3,-benzothiadiazole;

5-ethyl-4-(2-imidazolin-2-yl-amino)-2,1,3,-benzothiadiazole, and

5-bromo4-(2-imidazolin-2-yl-amino)-2,1,3,-benzothiadiazole.

The most preferred compound of formula I for use in the invention is5-chloro-4-(2-imidazolin-2-yl-amino)-7-methyl-2,1,3,-benzothiadiazole,alternatively known as5-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-2,1,3-benzothiadazol-4-amine,DS-103-282, Sirdalud and Ternelin.

Processes for the preparation of the compounds of formula I is describedin the literature; for example, in U.S. Pat. No. 3,843,668.

The COX-2 inhibitors used in the pharmaceutical compositions andtreatment methods of the present invention are typically those whichhave an IC₅₀ for COX-2 inhibition less than about 2 μM and an IC₅₀ forCOX-1 inhibition greater than about 5 μM, e.g. when measured in theassays described by Brideau et al.in Inflamm. Res. 45:68-74 (1996).Preferably the COX-2 inhibitor has a selectivity ratio of at least 10,more preferably at least 40, for COX-2 inhibition over COX-1 inhibition.

Thus, for example, suitable COX-2 inhibitors for use in the inventionmay include the following compounds or derivatives thereof or apharmaceutically acceptable salt thereof, or any hydrate thereof:rofecoxib, etoricoxib, celecoxib, valdecoxib, parecoxib, or a5-alkyl-2-arylaminophenylacetic acid derivative COX-2 inhibitor, e.g. offormula V as defined below.

Alternative classes of COX-2 inhibitor compounds for use in theinvention include those described in U.S. Pat. No. 6,136,804 (Merck).

COX-2 inhibitors of formula V are particularly preferred for use in thepresent invention.

Thus in preferred embodiments the COX-2 inhibitor for use in the presentinvention comprises a compound of formula V

wherein R is methyl or ethyl;

-   -   R₁ is chloro or fluoro;    -   R₂ is hydrogen or fluoro;    -   R₃ is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy        or hydroxy,    -   R₄ is hydrogen or fluoro; and    -   R₅ is chloro, fluoro, trifluoromethyl or methyl.

Above and elsewhere in the present description the terms “abenzothiadiazole derivative” and “COX-2 inhibitor” include, asappropriate, pharmaceutically acceptable salts and esters thereof.

Particularly preferred compounds of formula V are those wherein R ismethyl or ethyl; R₁ is chloro or fluoro; R₂ is hydrogen; R₃ is hydrogen,fluoro, chloro, methyl or hydroxy, R₄ is hydrogen; and R₅ is chloro,fluoro or methyl; pharmaceutically acceptable salts thereof; andpharmaceutically acceptable esters thereof.

A particularly preferred embodiment relates to the compounds of formulaV wherein R is methyl or ethyl; R₁ is fluoro; R₂ is hydrogen; R₃ ishydrogen, fluoro or hydroxy, R₄ is hydrogen; and R₅ is chloro;pharmaceutically acceptable salts thereof; and pharmaceuticallyacceptable prodrug esters thereof

Another particularly preferred embodiment of the invention relates tocompounds of formula V wherein R is ethyl or methyl; R₁ is fluoro; R₂ ishydrogen or fluoro; R₃ is hydrogen, fluoro, ethoxy or hydroxy; R₄ ishydrogen or fluoro; and R₅ is chloro, fluoro or methyl; pharmaceuticallyacceptable salts thereof; and pharmaceutically acceptable prodrug estersthereof.

Further are said compounds wherein R is methyl or ethyl; R₁ is fluoro;R₂-R₄ are hydrogen or fluoro; and R₅ is chloro or fluoro;pharmaceutically acceptable salts thereof; and pharmaceuticallyacceptable prodrug esters thereof.

A further embodiment of the invention relates to the compounds offormula V wherein R is methyl or ethyl; R₁ is fluoro; R₂ is fluoro; R₃is hydrogen, ethoxy or hydroxy; R₄ is fluoro; and R₅ is fluoro;pharmaceutically acceptable salts thereof; and pharmaceuticallyacceptable prodrug esters thereof.

Another embodiment of the invention relates to the compounds of formulaV wherein R is methyl; R₁ is fluoro; R₂ is hydrogen; R₃ is hydrogen orfluoro; R₄ is hydrogen; and R₅ is chloro; pharmaceutically acceptablesalts thereof; and pharmaceutically acceptable prodrug esters thereof

Particularly preferred embodiments of the invention relate to compoundsof formula V

(a) wherein R is methyl; R₁ is fluoro; R₂ is hydrogen; R₃ is hydrogen;R₄ is hydrogen; and R₅ is chloro; pharmaceutically acceptable saltsthereof; and pharmaceutically acceptable prodrug esters thereof;

(b) wherein R is methyl; R₁ is fluoro; R₂ is hydrogen; R₃ is fluoro; R₄is hydrogen; and R₅ is chloro; pharmaceutically acceptable saltsthereof; and pharmaceutically acceptable prodrug esters thereof;

(c) wherein R is ethyl; R₁ is fluoro; R₂ is fluoro; R₃ is hydrogen; R₄is fluoro; and R₅ is fluoro; pharmaceutically acceptable salts thereof;and pharmaceutically acceptable prodrug esters thereof; and

(d) wherein R is ethyl; R₁ is chloro; R₂ is hydrogen; R₃ is chloro; R₄is hydrogen; and R₅ is methyl; pharmaceutically acceptable saltsthereof; and pharmaceutically acceptable prodrug esters thereof.

Most preferably the COX-2 inhibitor of formula V is5-methyl-2-(2′-chloro-6′-fluoroanilino)phenylacetic acid, or a salt orester thereof

Pharmaceutically acceptable prodrug esters of the compounds of formula Vare ester derivatives which are convertible by solvolysis or underphysiological conditions to the free carboxylic acids of formula V. Suchesters are e.g. lower alkyl esters (such as the methyl or ethyl ester),carboxy-lower alkyl esters such as the carboxymethyl ester,nitrooxy-lower alkyl esters (such as the 4-nitrooxybutyl ester), and thelike. Preferred prodrugs are the compounds of formula Ia

wherein R and R₁-R₅ have meaning as defined hereinabove for compounds offormula V; and pharmaceutically acceptable salts thereof.

Compounds of formula V and Va and their synthesis are described inpublished international patent applications Nos. WO 99/11605 and WO01/23346, the teachings of which are incorporated herein by reference.

Pharmacologically acceptable salts of benzothiadiazole derivatives andCOX-2 inhibitors are preferably salts with bases, conveniently metalsalts derived from groups Ia, Ib, IIa and IIb of the Periodic Table ofthe Elements, including alkali metal salts, e.g. potassium andespecially sodium salts, or alkaline earth metal salts, preferablycalcium or magnesium salts, and also ammonium salts with ammonia ororganic amines.

The Agents of the Invention, i.e. the COX-2 inhibitor and thebenzothiadiazole derivative are preferably used in the form ofpharmaceutical preparations that contain the relevant therapeuticallyeffective amount of of each active ingredient (either separately or incombination) optionally together with or in admixture with inorganic ororganic, solid or liquid, pharmaceutically acceptable carriers which aresuitable for administration. The Agents of the Invention may be presentin the same pharmaceutical compositions, though are preferably inseparate pharmaceutical compositions. Thus the active ingredients may beadministered at the same time (e.g. simultaneously) or at differenttimes (e.g. sequentially) and over different periods of time, which maybe separate from one another or overlapping.

The pharmaceutical compositions may be, for example, compositions forenteral, such as oral, rectal, aerosol inhalation or nasaladministration, compositions for parenteral, such as intravenous orsubcutaneous administration, or compositions for transdermaladministration (e.g. passive or iontophoretic).

The particular mode of administration and the dosage may be selected bythe attending physician taking into account the particulars of thepatient, especially age, weight, life style, activity level, and diseasestate as appropriate

Preferably, both the COX-2 inhibitor and benzothiadiazole derivativepharmaceutical compositions are adapted for oral or parenteral(especially oral) administration. Intravenous and oral, first andforemost oral, adminstration is considered to be of particularimportance. Preferably the COX-2 inhibitor active ingredient is in oralform.

The dosage of COX-2 inhibitor administered is dependent on the speciesof warm-blooded animal (mammal), the body weight, age and individualcondition, and on the form of administration. A unit dosage for oraladministration to a mammal of about 50 to 70 kg may contain betweenabout 5 and 1500 mg, e.g. from 100-1000 mg, preferably 200-800 mg of theactive ingredient.

COX-2 inhibitor formulations in single dose unit form contain preferablyfrom about 1% to about 90%, and formulations not in single dose unitform contain preferably from about 0.1% to about 20%, of the activeingredient. Single dose unit forms such as capsules, tablets or dragéescontain e.g. from about 1 mg to about 1500 mg of the active ingredient.

COX-2 inhibitor formulations in single dose unit form contain preferablyfrom about 1% to about 90%, and formulations not in single dose unitform contain preferably from about 0.1% to about 20%, of the activeingredient. Single dose unit forms such as capsules, tablets or dragéescontain e.g. from about 1 mg to about 1500 mg of the active ingredient.

Similarly the dosage of benzothiadiazole derivative administered isdependent on the species of warm-blooded animal (mammal), the bodyweight, age and individual condition, and on the form of administration.In general, the daily dosage of benzothiadiazole derivative variesbetween about 0.01 mg/kg and about 100 mg/kg. Suitable unit dosageforms, such as dragées, tablets or suppositories, preferably containfrom about 10 to about 400 mg of benzothiadiazole derivative. Dosageunits for oral administration preferably contain between 10% and 90% byweight of benzothiadiazole derivative.

Pharmaceutical preparations for enteral and parenteral administrationare, for example, those in dosage unit forms, such as dragées, tabletsor capsules and also ampoules. They are prepared in a manner known perse, for example by means of conventional mixing, granulating,confectioning, dissolving or lyophilising processes. For example,pharmaceutical preparations for oral administration can be obtained bycombining the active ingredient with solid carriers, where appropriategranulating a resulting mixture, and processing the mixture orgranulate, if desired or necessary after the addition of suitableadjuncts, into tablets or dragée cores.

Other orally administrable pharmaceutical preparations are dry-filledcapsules made of gelatin, and also soft, sealed capsules made of gelatinand a plasticiser, such as glycerol or sorbitol. The dry-filled capsulesmay contain the active ingredient in the form of a granulate, forexample in admixture with fillers, such as lactose, binders, such asstarches, and/or glidants, such as talc or magnesium stearate, and,where appropriate, stabilisers. In soft capsules the active ingredientis preferably dissolved or suspended in suitable liquids, such as fattyoils, paraffin oil or liquid polyethylene glycols, it being possiblealso for stabilisers to be added.

Parenteral formulations are especially injectable fluids that areeffective in various manners, such as intravenously, intramuscularly,intraperitoneally, intranasally, intradermally or subcutaneously. Suchfluids are preferably isotonic aqueous solutions or suspensions whichcan be prepared before use, for example from lyophilised preparationswhich contain the active ingredient alone or together with apharmaceutically acceptable carrier. The pharmaceutical preparations maybe sterilised and/or contain adjuncts, for example preservatives,stabilisers, wetting agents and/or emulsifiers, solubilisers, salts forregulating the osmotic pressure and/or buffers.

Suitable formulations for transdermal application include an effectiveamount of the active ingredient with carrier. Advantageous carriersinclude absorbable pharmacologically acceptable solvents to assistpassage through the skin of the host. Characteristically, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the active ingredient of the skin ofthe host at a controlled and predetermined rate over a prolonged periodof time, and means to secure the device to the skin.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon.

EXAMPLES A. Formulation Examples Example 1

TABLE 1 Amount per 200 mg Ingredient tablet batch (kg) Core Granulation5-methyl-2-(2′-chloro-6′- 50** fluoroanilino)phenylacetic acid drugsubstance Microcrystalline cellulose, NF (PH 12.85 101) Lactosemonohydrate, NF 11.65 Croscarmellose sodium, NF  1 Povidone, USP  4Titanium dioxide, USP  2 Water, purified***, USP 20.375 Extra-granularPhase Microcrystalline cellulose, NF (PH 13 102) Croscarmellose sodium,NF  3 Titanium dioxide, USP  2 Magnesium stearate, NF  0.5 CoatingOpadry white  2.801**** Opadry yellow  2.0**** Opadry red  0.4****Opadry black  0.0504**** Water, purified***, USP 29.758******The weight of drug substance is taken with reference to the driedsubstance (100 percent) on the basis of the assay value (factorization).The difference in weight is adjusted by the amount of microcrystallinecellulose used.***Removed during processing.****Includes a 50% excess for loss during the coating process.

Table 1, above, sets out the formula for a batch of approximately250,000 immediate release film-coated tablets of5-methyl-2-(2′-chloro-6′-fluoroanilino)-phenylacetic acid. To make thetablets, titanium dioxide is dispersed in water, followed by theaddition of povidone and mixing for 20 minutes to make apovidone/titanium dioxide suspension. The drug substance, lactose,microcrystalline cellulose, and croscarmellose are mixed in a high shearmixer (e.g., a Collette Gral) for 5 minutes to form a drug mixture. Thedrug mixture is granulated in the high shear mixer with thepovidone/titanium dioxide suspension. The suspension is pumped at a rateof 3 kg/min into the drug mixture. The resulting mixture is mixed anadditional 90 seconds after all the suspension is added. The wetgranulation is dried in a fluid bed dryer, using an inlet airtemperature of 50° C. The residual water target is 3.5% (with apermissible range of 2.5-4.5%). The dried granulation is passed througha screen using a mill (oscillator) and a 30 mesh screen. The previoussteps are repeated to make a second granulation.

The extra-granular phase titanium dioxide is passed through a 60 meshhand screen. The dry granulations are mixed with the extra-granularphase microcrystalline cellulose, croscarmellose sodium and titaniumdioxide in a twin shell mixer for 300 revolutions to form a penultimatemixture. Magnesium stearate is passed through a 60 mesh hand screen andis mixed with the penultimate mixture in a twin shell mixer for 50revolutions to form a tableting mixture. The tableting mixture ispressed into tablets using a tablet press and oval punches.

The coating powders (Opadry) are mixed with purified water to make a 15%w/w coating suspension. The tablets are film coated with the coatingsuspension in a coating pan using 60° C. to 75° C. inlet airtemperature.

Table 2 sets out the contents of a 200 mg5-methyl-2-(2′-chloro-6′-fluoroanilino)phenylacetic acid film-coatedtablet. TABLE 2 Theoretical Ingredient amount [mg] Function Core5-methyl-2-(2′-chloro-6′- 200 Active fluoroanilino)phenylaceticsubstance acid drug substance Microcrystalline cellulose (PH 51.4 Filler101) Lactose 46.6 Filler Povidone 16 Binder Titanium dioxide 8 ColorCroscarmellose sodium 4 Disintegrant Water, purified* Q.S. Granulatingliquid Extragranular phase Microcrystalline cellulose (PH 52 Filler 102)Croscarmellose sodium 12 Disintegrant Titanium dioxide 8 Color Magnesiumstearate 2 Lubricant Core weight 400 Coating Opadry white (00F18296)7.4676 Color Opadry yellow (00F12951) 5.3312 Color Opadry red (00F15613)1.0668 Color Opadry black (00F17713) 0.1344 Color Water, purified* Q.S.Coating solvent Total weight 414*removed during processing

In addition, the tablet formulations may contain5-methyl-2-(2′-chloro-6′-fluoroanilino)benzyl alcohol and/or5-methyl-2-(2′-chloro-6′-fluoroanilino)benzoic acid in an amount betweenabout 0.01 and 2% by weight, more specifically between about 0.1 and 1

Example 2

An alternative formulation is as set out in Table 3, with informationabout as percentage w/w, mg/dose, and kg/50,000 tablet batch. TABLE 3Alternative formulation composition % w/w Ingredient Mg/dose Kg/batchGranulation 65.04 5-methyl-2-(2′-chloro-6′-fluoroanilino) 400.00 20.00phenylacetic acid drug substance 2.15 Croscarmellose sodium, NF(Ac-Di-Sol) 13.22 0.661 6.60 Povidone K30, USP 40.59 2.029 18.12Purified water, USP* Qs Qs Blending 23.56 Microcrystalline Cellulose, NF(Avicel 144.90 6.066 PH 102) 2.15 Croscarmellose sodium, NF (Ac-Di-Sol)13.22 0.553 0.50 Magnesium Stearate, NF (vegetable 3.07 0.128 source)Film Coating 84.46 Opadry, Global White 00F18296 15.2028 0.296637 14.03Opadry, Global Red 00F15613 2.5254 0.049275 1.51 Opadry, Global Black00F17713 0.2718 0.005303 Purified Water, USP* Qs 1.990218 Film CoatedTablet Weight 633.00*Does not appear in final product. Percentage of water added used forgranulation based on the dry weight of drug substance and croscarmellosesodium.

The batch is granulated as described in Example 1. The granulation isdried to residual moisture (% LOD) of 1.79%. The formulation process isthe same as for the development batches as described above, except forthe additional step of coating with Opadry in a coating pan. The coatingpowders (Opadry) are mixed with purified water to make a 15% w/w coatingsuspension. The tablets are film coated with the coating suspension in acoating pan using 60° C. to 75° C. inlet air temperature. Based onfriability data, a target force of 18 KN (16-20 KN range) is used tocompress the remainder of the batch, resulting in acceptable friability(less than 0.5%) and the disintegration times of less than 5 mins. Theejection force is approximately 800 N throughout the compression run.This demonstrates that the blend is lubricated adequately. Nopicking/sticking is observed on the punch surfaces after 225 minutes.Thus, a smaller size tablet with high drug loading (65%) is achievedusing a high shear granulation process, using 17×6.7 mm ovaloid toolingto get tablets with acceptable hardness and friability characteristics.

In addition, the tablet formulations may contain5-methyl-2-(2′-chloro-6′-fluoroanilino)benzyl alcohol and/or5-methyl-2-(2′-chloro-6′-fluoroanilino)benzoic acid in an amount betweenabout 0.01 and 2% by weight, more specifically between about 0.1 and 1%.

Example 3

Wet Granulated Tablet Composition Amount per tablet Ingredient 25 mgCOX-2 inhibitor 79.7 mg Microcrystalline cellulose 79.7 mg Lactosemonohydrate 6 mg Hydroxypropyl cellulose 8 mg Croscarmellose sodium 0.6mg Iron oxide 1 mg Magnesium stearate

Tablet dose strengths of between 5 and 125 mg can be accomodated byvarying total weight, and the ratio of the first three ingredients.Generally it is preferable to maintain a 1:1 ratio for microcrystallinecellulose: lactose monohydrate.

Example 4

Hard Gelatine Capsule Composition Amount per capsule Ingredient 25 mgCOX-2 inhibitor 37 mg Microcrystalline cellulose 37 mg Lactose anhydrate1 mg Magnesium stearate 1 capsule Hard gelatin capsule

Capsule dose strengths of between 1 and 50 mg can be accomodated byvarying total fill weight, and the ratio of the first three ingredients.Generally it is preferable to maintain a 1:1 ratio for microcrystallinecellulose:lactose monohydrate.

Example 5

Oral Solution Amount per 5 mL Ingredient 50 mg COX-2 inhibitor to 5 mLwith Polyethylene oxide 400

Example 6

Intravenous Infusion Amount per 200 mL dose Ingredient 1 mg COX-2inhibitor 0.2 mg Polyethylene oxide 400 1.8 mg Sodium chloride to 200 mLPurified water

Example 7

Benzothiadiazole Derivative Formulations

An example of a tablet composition comprises 40 mg of5-chloro-4-(2-imidazolin-2-yl-amino)-2,1,3-benzothiazole, 70 mg oflactose, 5 mg of maize starch, 5 mg of talc and 0.1 mg of magnesiumstearate.

Example 8 Treatment of Patients

Assumptions: 1) Two formulations: 200 mg Prexige plus 300 mg Sirdalud200 mg Prexige plus 600 mg Sirdalud 2) b.i.d. dosing 3) limitedtitration 4) effective dose Sirdalud = 900-1200 mg/day effective dosePrexige = 400 mg/day 5) sample size would have to estimated by astatistician 6) trial timeline is set up to achieve POC but possibly notstatistical significance

Design: double-blind, placebo-controlled, parallel group, multicenter

Duration: 4 to 6 weeks including screening

Patient population:

-   -   inclusion criteria—male or female ≧to 18 years old        -   low back pain (below T6 and above gluteal fold) that may            radiate to leg        -   pain lasting more than three months        -   pain present on five out of seven days        -   VAS score ≧to 40 mm on four of the last seven days        -   comprehensive history and physical examination including            focused neurological examination    -   exclusion criteria—unstable spinal segment        -   progressive neurological deficits        -   excluded drugs: all other NSAIDs, opioids, TCAs, AEDs, oral            steroids except for treatment of asthma or skin conditions,            steroid injections        -   other pain conditions that may interfere with assessment of            the low back pain        -   patients previously treated with either Prexige or Sirdalud        -   patients with hypersensitivity to carbamazepine,            oxcarabazepine or lumiracoxib and other non-steroidal            anti-inflammatories including aspirin        -   patients with active disability compensation claims or any            litigation related to their radiculopathic pain.

Variables:

-   -   primary efficacy variable—VAS    -   secondary efficacy variables—responder rate, sleep assessment,        SF-36, POMS, assessment of back mobility and low-back pain        specific QOL

Suggested visit schedule: visit 1 (day − 14 to day − 1) screening visit2 (day 1) randomization, titration and treatment visit 3 (day 21)withdrawal visit 4 (day 28) final visit

The withdrawal phase can be eliminated to give 4 weeks total treatment(I week titration, 3 weeks maintenance).

Titration and maintenance dosing schedule: Day AM Dose^(a) PM Dose^(a)Total Daily Doses^(a) 1 0 200/300 200/300 2 200/300 200/300 400/600 3200/300 200/300 400/600 4 200/300 200/600 400/900 5 200/300 200/600400/900 6 200/600 200/600  400/1200  7-21 200/600 200/600  400/120022-28 0 0 0^(a)expressed as mg Prexige/mg Sirdalud

1. A pharmaceutical composition for treatment of pain, which comprisesin combination a benzothiadiazole derivative of formula I

wherein each R1, R2 and R3 independently, is hydrogen, halogen, C₁-C₇alkyl, C₁-C₇ alkoxy, nitro, cyano, hydroxy or C₁-C₇ alkylthio; and aCOX-2 inhibitor for simultaneous, sequential or separate use. 2.(canceled)
 3. (canceled)
 4. A method of treating a patient sufferingfrom pain comprising administering to the patient an effective amount ofa benzothiadiazole derivative of formula I,

wherein each R1, R2 and R3 independently, is hydrogen, halogen, C₁-C₇alkyl, C₁-C₇ alkoxy, nitro, cyano, hydroxy or C₁-C₁ alkylthio, and aneffective amount of a COX-2 inhibitor.
 5. A package comprising abenzothiadiazole derivative of formula I,

wherein each R1, R2 and R3 independently, is hydrogen, halogen, C₁-C₇alkyl, C₁-C₇ alkoxy, nitro, cyano, hydroxy or C₁-C₇ alkyithio, fortreatment of pain according to a method wherein said benzothiadiazolederivative of formula I is used in combination with a COX-2 inhibitorfor treatment of pain, or a package comprising a COX-2 inhibitor fortreatment of pain according to a method wherein said COX-2 inhibitor isused combination with a benzothiadiazole derivative of formula I asdefined above.
 6. A composition according to claim 1 in which the COX-2inhibitor is selected from the group consisting of rofecoxib,etoricoxib, celecoxib, valdecoxib, parecoxib, and a5-alkyl-2-arylaminophenylacetic acid derivative COX-2 inhibitor, or apharmaceutically acceptable salt, or any hydrate thereof.
 7. Acomposition according to claim 1 in which the COX-2 inhibitor is acompound of formula V

wherein R is methyl or ethyl; R₁ is chloro or fluoro; R₂ is hydrogen orfluoro; R₃ is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxyor hydroxy; R₄ is hydrogen or fluoro; and R₅ is chloro, fluoro,trifluoromethyl or methyl, or a pharmaceutically acceptable salt orester thereof.
 8. A composition according to claim 7 in which the COX-2inhibitor is 5-methyl-2-(2′-chloro-6′-fluoroanilino)phenylacetic acid,or a pharmaceutically acceptable salt or ester thereof.
 9. A compositionaccording to claim 1 in which the benzothiadiazole derivative is5-chloro4-(2-imidazol-2-ylamino)-2,1,3-benzothiadiazole.